Diarrhea or diarrhoea is defined by the World Health Organization as a condition of having at least three loose or liquid bowel movements each day or as having more stool than is normal for that person.1 It often lasts for a few days and can result in dehydration due to fluid loss. 1 See Diarrhoeal Disease Fact Sheet N°330, World Health Organization, April 2013.
The most common cause of diarrhea is an infection of the intestines due to a virus, bacteria, or parasite, a condition known as gastroenteritis. These infections are often acquired from food or water that has been contaminated by stool, or directly from another person who is infected. A number of non-infectious causes may also result in diarrhea including: hyperthyroidism, lactose intolerance, inflammatory bowel disease, a number of medications, and irritable bowel syndrome among others.
Prevention of infectious diarrhea is by improved sanitation, clean drinking water, and hand washing. Oral rehydration solution (ORS), which is clean water with modest amounts of salt and sugar, along with zinc tablets are often employed. In those with severe dehydration, intravenous fluids may be required.
About 1.7 to 5 billion cases of diarrhea occur per year.2 It is most common in developing countries were young children get diarrhea on average three times a year. Worldwide, as of 2012, it is the second most common cause of death in children less than five (0.76 million or 11%).3 Frequent episodes of diarrhea are also a common cause of malnutrition and the most common cause in those less than five years of age. Other long term problems that can result include poor physical and intellectual development. 2 See Diarrhoea: why children are still dying and what can be done, The United Nations Children's Fund, World Health Organization, 2009.3 See Diarrhoeal Disease Fact Sheet N°330, World Health Organization, April 2013.
Chronic diarrhea can be the part of the presentations of a number of chronic medical conditions affecting the intestine. Common causes include ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome and bile acid malabsorption.
While antibiotics are beneficial in certain types of acute diarrhea, they are usually not used except in specific situations as some bacteria develop antibiotic resistance. Antibiotics themselves can also cause diarrhea, and antibiotic-associated diarrhea is the most common adverse effect associated with treatment using general antibiotics.
Anti-motility agents like loperamide are also effective at reducing the number of stools but not the duration of disease.4 4 See Dupont, H. L., Acute infectious diarrhea in immunocompetent adults, New England Journal of Medicine, 2014, 370:1532-40.
Probiotics are “friendly” bacteria that have proven beneficial in the treatment of diarrhea.5 5 See Allen S. J., et al., Probiotics for treating acute infectious diarrhoea (Review), Cochrane Database of Systematic Reviews 2010, Issue 11. Art. No.: CD003048. DOI: 10.1002/14651858.CD003048.pub3.
Racecadotril (shown below), also known as acetorphan or (RS)-benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect, i.e., it reduces the secretion of water and electrolytes into the intestine. Racecadotril exhibits an original intestinal antisecretory action, by protecting endogenous enkephalines against the degradation thereof. By improving the biological activity of these neuropeptides at the delta opiate receptors, racecadotril reduces the hydroelectric flows in the intestinal lumen, which flows are otherwise increased in diarrheal diseases of various origins. Racecadotril is selective in that the intestinal hypersecretion (or reduced electrolyte reabsorption) which characterizes diarrhoea and is responsible for severe states of dehydration is greatly reduced without altering the transit.6 This model contributes to the particularly beneficial properties of racecadotril, as has already been shown in clinical trials and post-marketing study.7 6 Matheson A. J., et al., Drugs 2000, 59, 829; Schwartz J. C., Int. Antimicrob. Agents, 2000, 14, 81.7 Lecomte et al., Int. J. Antimicrob. Agents, 2000, 14, 81.
In clinical trials as well as in standard practice, racecadotril is generally administered in 100 mg capsules, taken three times a day, in order to ensure complete inhibition of the targeted peptidase throughout the day without interruption. A twice a day (b.i.d.) tablet has also been studied.
Racecadotril is sold in the market in a number of countries under the tradename HIDRASEC® (trademark of SmithKline Beecham) and TIORFAN® (trademark of Societe Civile de Recherche Bioprojet). One marketed form is a dry powder filled into a hard gelatin capsule.
It is desirable to have additional formulations of racecadotril.
Dexecadotril (shown below), also known as R-acetorphan or N—[(R)-2-Benzyl-3-(acetylthio)propionyl]glycine benzyl ester; N—[(R)-2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]glycine benzyl ester is the R enantiomer of racecadotril.
Ecadotril (shown below), also known as S-acetorphan or N—[(S)-2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]glycinebenzyl ester is the S enantiomer of racecadotril.


Throughout the disclosure “cadotril” will be used to include racecadotril, dexecadotril and/or ecadotril.
Racecadotril is a class II drug (as per Biopharmaceutical Classification System) with poor aqueous solubility and dissolution rate limited absorption. Racecadotril undergoes hydrolysis when it comes into contact with water. There are two major pairs of hydrolysis products, i.e., benzyl alcohol and EP Impurity C and thioacetic acid and EP Impurity G. Thiorphan, which is a product of the hydrolysis reaction, is not a major degradation product. Thiorphan (shown below) is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinase.

U.S. Pat. No. 4,513,009 to Bioprojet discloses racecadotril and some of its therapeutic applications.
U.S. Pat. Nos. 5,331,008; 5,296,509; 5,208,255; and 5,136,076 to Bioprojet disclose enantiomeric forms of racecadotril.
U.S. Pat. No. 6,919,093 to Bioprojet discloses a dry powder racecadotril formulation that comprises coated granules and specified excipients.
U.S. Pat. No. 8,222,294 to Bioprojet discloses a combination that comprises racecadotril or dexecadotril with ondansetron or granisetron.
U.S. Pat. No. 8,318,203 to Bioprojet discloses a racecadotril tablet that comprises a coated core and specified excipients.
U.S. Application No. 20130331423 to Bioprojet discloses an aqueous suspension that comprises racecadotril.
WO2001097803 to GlaxoSmithKline discloses a granulate formulation comprising racecadotril and specified excipients.
U.S. Application No. 20020028248 to Tsukada et al. discloses rapid-release microdispersible preparation containing ecadotril.
CN102133186 to Hainan Meida Pharmaceutical Co. discloses a liposome racecadotril solid preparation that comprises specified ingredients in specified relative weight ratios.
CN101103960 to Hainan Shengke Life Scientific Research Institute and CN102327234 to Hainan Honz Pharmaceutical Co., Ltd. each disclose racecadotril containing dry suspensions that comprises specified ingredients.
CN101264065 to Yancheng Suhai Pharmaceutical Co., Ltd. discloses a racecadotril dropping pill that comprises specified ingredients in specified weight ratios.
IN20110127511, IN20110127411 and IN201101191211 to Akums disclose pharmaceutical formulations that comprise (1) racecadotril and (2) ofloxacin and/or ornidazole.
IN20080088413 to Torrent Pharmaceuticals Limited discloses a resinate complex that comprises racecadotril.
IN20060165213 to Torrent Pharmaceuticals Limited discloses a taste-masked composition that comprises particles comprising racecadotril and a low melting excipient. The composition is prepared by dispersing racecadotril in a melt; cooling the dispersion at room temperature to form a solidified mass; and milling the solidified mass to obtain racecadotril particles.
U.S. Application No. 20140005262 to McNeil-PPC, Inc. discloses a composition that comprises racecadotril, at least one surfactant and a lipid.
U.S. Application No. 20140005261 to McNeil-PPC, Inc. discloses a liquid composition that comprises racecadotril and cyclodextrin.
EP2749270 discloses a dispersible tablet comprising racecadotril coated with an acrylic acid polymer or a cellulose polymer by a wet granulation method.
There continues to be a need for cadotril products having the attributes discussed above.